The present invention, in some embodiments thereof, relates to antibody combinations and use of same in treating cancer.
ErbB-2/HER2 is a member of the epidermal growth factor receptor (EGFR) family. When trans-activated, ErbB-2/HER2 stimulates several downstream signaling cascades, including the mitogen-activated protein kinase cascade [reviewed in (1)]. This ligand-less receptor is moderately expressed in normal adult tissues, where it regulates cell growth and differentiation. By contrast, amplification of the corresponding gene and consequent overexpression of the HER2/ErbB-2 protein have been reported in 20-30% of tumors of the breast (2-4) and ovary (4). In general, erbB-2 gene amplification associates with enhanced metastatic potential and poor prognosis. Because ErbB-2 is expressed at relatively low levels in normal tissues, it makes an attractive target for immunotherapy. This was originally demonstrated in animals by Greene and colleagues (5), who targeted Neu, the rodent form of ErbB-2, and later developed into a widely used clinical strategy [reviewed in (6)]. Nevertheless, the molecular mechanisms underlying the growth inhibitory effects of anti-ErbB-2 monoclonal antibodies (mAbs) are not completely understood. Several mechanisms of action have been proposed, including immune mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytototoxicity (CDC), increased cancer cell apoptosis and interference with signaling cascades [reviewed in (6)].
Clinical studies established that Trastuzumab (Herceptin®), a humanized mAb directed against ErbB-2, is active against ErbB-2-overexpressing metastatic breast cancer, leading to its approval for clinical use (7). The objective response rates to Trastuzumab monotherapy is relatively low (approximately 15%) and short lived (a median duration of 9 months) (8). On the other hand, mAbs seem to display a synergistic effect when combined with chemotherapy, probably due to interruption of ErbB-2-driven survival pathways (9). Still another strategy, relevant to pancreatic cancer, combines antibodies to EGFR and to ErbB-2 (10).
Yet another approach for improving the efficacy of antibody therapy refers to the use of mAb combinations. Indeed a number of studies have been effected using at least two antibody combinations directed at distinct epitopes of ErbB-2 [Drebin J. A. et al., Oncogene 2(3):273-277, 1988; Kasprzyk et al., Cancer Res. 52(10):2771-2776, 1992; Harwerth et al., Br. J. Cancer 68(6):1140-1145, 1993; Spiridon et al. Clin. Cancer Res. 8:1720-1730, 2002; Friedman et al. Proc. Natl. Acad. Sci. (2005) 102:1915-1920; and U.S. patent application Ser. No. 11/342,615]